The United States government has rights in this invention by virtue of grant No. GM-33328 awarded by the National Institutes of Health.
This invention relates to a process for the preparation of 1-carba(1-dethia)-3-cephem-4-carboxylic acids and derivatives thereof. In particular, it relates to an asymmetric process for the preparation of 1-carba(1-dethia)-3-cephem-4-carboxylic acids and to 1-substituted-3.beta.-(4(S)-aryloxazolidin-2-one-3-yl)-4.beta.-styryl (or substituted styryl)azetidin-2-one intermediates useful therein. Related 4-substituted 3.beta.-(4(S)-aryloxazolidin-2-one-3-yl)azetidin-2-one compounds, useful in the asymmetric synthesis of other .beta.-lactam antibiotics, are provided.
The 1-carba(1-dethia)-3-cephem-4-carboxylic acids, hereinafter 1-carbacephalosporins, possess the 4,6 bicyclic ring system represented by the following structural formula ##STR1## wherein the arbitrary numbering system employed according to the cepham nomenclature system is used for convenience as indicated.
The preparation of 1-carbacephalosporanic acids and C-3 substituted methyl derivatives thereof is taught broadly by Christensen et al., U.S. Pat. No. 4,226,866. Hirata et al., U.K. Patent Application No. 2041923 teach a process for preparing 3-halo and 3-H 1-carbacephalosporins; and Hatanaka et al., Tetrahedron Letters, Vol. 24, No. 44, pp 4837-4838 (1983), teach a process for preparing a 3-hydroxy-(.+-.)-1-carbacephalosporin.
The 1-carbacephalosporins thus far have not been obtained from natural sources, for example, as microbial metabolites. Accordingly methods for the total synthesis of these promising compounds are highly desirable, particularly methods which are adaptable to large scale manufacture.